Emerging pharmacotherapy of tinnitus

Tinnitus, the perception of sound in the absence of an auditory stimulus, is perceived by about 1 in 10 adults, and for at least 1 in 100, tinnitus severely affects their quality of life. Because tinnitus is frequently associated with irritability, agitation, stress, insomnia, anxiety and depression, the social and economic burdens of tinnitus can be enormous. No curative treatments are available. However, tinnitus symptoms can be alleviated to some extent. The most widespread management therapies consist of auditory stimulation and cognitive behavioral treatment, aiming at improving habituation and coping strategies. Available clinical trials vary in methodological rigor and have been performed for a considerable number of different drugs. None of the investigated drugs have demonstrated providing replicable long-term reduction of tinnitus impact in the majority of patients in excess of placebo effects. Accordingly, there are no FDA or European Medicines Agency approved drugs for the treatment of tinnitus. However, in spite of the lack of evidence, a large variety of different compounds are prescribed off-label. Therefore, more effective pharmacotherapies for this huge and still growing market are desperately needed and even a drug that produces only a small but significant effect would have an enormous therapeutic impact. This review describes current and emerging pharmacotherapies with current difficulties and limitations. In addition, it provides an estimate of the tinnitus market. Finally, it describes recent advances in the tinnitus field which may help overcome obstacles faced in the pharmacological treatment of tinnitus. These include incomplete knowledge of tinnitus pathophysiology, lack of well-established animal models, heterogeneity of different forms of tinnitus, difficulties in tinnitus assessment and outcome measurement and variability in clinical trial methodology. © 2009 Informa UK Ltd.Fil: Langguth, Berthold. Universitat Regensburg; AlemaniaFil: Salvi, Richard. State University of New York; Estados UnidosFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentin

Pope Leo IX: A reforming pope?

No abstract available

Field Production and Functional Evaluation of Chloroplast-Derived Interferon-α2b

Type I interferons (IFNs) inhibit viral replication and cell growth and enhance the immune response, and therefore have many clinical applications. IFN-α2b ranks third in world market use for a biopharmaceutical, behind only insulin and erythropoietin. The average annual cost of IFN-α2b for the treatment of hepatitis C infection is $26 000, and is therefore unavailable to the majority of patients in developing countries. Therefore, we expressed IFN-α2b in tobacco chloroplasts, and transgenic lines were grown in the field after obtaining United States Department of Agriculture Animal and Plant Health Inspection Service (USDA-APHIS) approval. Stable, site-specific integration of transgenes into chloroplast genomes and homoplasmy through several generations were confirmed. IFN-α2b levels reached up to 20% of total soluble protein, or 3 mg per gram of leaf (fresh weight). Transgenic IFN-α2b had similar in vitrobiological activity to commercially produced PEG-Intron™ when tested for its ability to protect cells against cytopathic viral replication in the vesicular stomatitis virus cytopathic effect (VSV CPE) assay and to inhibit early-stage human immunodeficiency virus (HIV) infection. The antitumour and immunomodulating properties of IFN-α2b were also seen in vivo . Chloroplast-derived IFN-α2b increased the expression of major histocompatibility complex class I (MHC I) on splenocytes and the total number of natural killer (NK) cells. Finally, IFN-α2b purified from chloroplast transgenic lines (cpIFN-α2b) protected mice from a highly metastatic tumour line. This demonstration of high levels of expression of IFN-α2b, transgene containment and biological activity akin to that of commercial preparations of IFN-α2b facilitated the first field production of a plant-derived human blood protein, a critical step towards human clinical trials and commercialization

Spaceflight Causes Increased Virulence of Serratia Marcescens on a Drosophila Melanogaster Host

Drosophila melanogaster, or the fruit fly, has long been an important organism for Earth-based research, and is now increasingly utilized as a model system to understand the biological effects of spaceflight. Studies in Drosophila melanogaster have shown altered immune responses in 3rd instar larvae and adult males following spaceflight, changes similar to those observed in astronauts. In addition, spaceflight has also been shown to affect bacterial physiology, as evidenced by studies describing altered virulence of Salmonella typhimurium following spaceflight and variation in biofilm growth patterns for the opportunistic pathogen Pseudomonas aeruginosa during flight. We recently sent Serratia marcescens Db11, a Drosophila pathogen and an opportunistic human pathogen, to the ISS on SpaceX-5 (Fruit Fly Lab-01). S. marcescens samples were stored at 4degC for 24 days on-orbit and then allowed to grow for 120 hours at ambient station temperature before being returned to Earth. Upon return, bacteria were isolated and preserved in 50% glycerol or RNAlater. Storage, growth, and isolation for ground control samples were performed using the same procedures. Spaceflight and ground samples stored in 50% glycerol were diluted and injected into 5-7-day-old ground-born adult D. melanogaster. Lethality was significantly greater in flies injected with the spaceflight samples compared to those injected with ground bacterial samples. These results indicate a shift in the virulence profile of the spaceflight S. marcescens Db11 and will be further assessed with molecular biological analyses. Our findings strengthen the conclusion that spaceflight impacts the virulence of bacterial pathogens on model host organisms such as the fruit fly. This research was supported by NASA's ISS Program Office (ISSPO) and Space Life and Physical Sciences Research and Applications (SLPSRA)

Catalysis over zinc-incorporated berlinite (ZnAlPO4) of the methoxycarbonylation of 1,6-hexanediamine with dimethyl carbonate to form dimethylhexane-1,6-dicarbamate

<p>Abstract</p> <p>Background</p> <p>The alkoxycarbonylation of diamines with dialkyl carbonates presents promising route for the synthesis of dicarbamates, one that is potentially 'greener' owing to the lack of a reliance on phosgene. While a few homogeneous catalysts have been reported, no heterogeneous catalyst could be found in the literature for use in the synthesis of dicarbamates from diamines and dialkyl carbonates. Because heterogeneous catalysts are more manageable than homogeneous catalysts as regards separation and recycling, in our study, we hydrothermally synthesized and used pure berlinite (AlPO₄) and zinc-incorporated berlinite (ZnAlPO₄) as heterogeneous catalysts in the production of dimethylhexane-1,6-dicarbamate from 1,6-hexanediamine (HDA) and dimethyl carbonate (DMC). The catalysts were characterized by means of XRD, FT-IR and XPS. Various influencing factors, such as the HDA/DMC molar ratio, reaction temperature, reaction time, and ZnAlPO₄/HDA ratio, were investigated systematically.</p> <p>Results</p> <p>The XRD characterization identified a berlinite structure associated with both the AlPO₄and ZnAlPO₄catalysts. The FT-IR result confirmed the incorporation of zinc into the berlinite framework for ZnAlPO₄. The XPS measurement revealed that the zinc ions in the ZnAlPO₄structure possessed a higher binding energy than those in ZnO, and as a result, a greater electron-attracting ability. It was found that ZnAlPO₄catalyzed the formation of dimethylhexane-1,6-dicarbamate from the methoxycarbonylation of HDA with DMC, while no activity was detected on using AlPO₄. Under optimum reaction conditions (i.e. a DMC/HDA molar ratio of 8:1, reaction temperature of 349 K, reaction time of 8 h, and ZnAlPO₄/HDA ratio of 5 (mg/mmol)), a yield of up to 92.5% of dimethylhexane-1,6-dicarbamate (with almost 100% conversion of HDA) was obtained. Based on these results, a possible mechanism for the methoxycarbonylation over ZnAlPO₄was also proposed.</p> <p>Conclusion</p> <p>As a heterogeneous catalyst ZnAlPO₄berlinite is highly active and selective for the methoxycarbonylation of HDA with DMC. We propose that dimethylhexane-1,6-dicarbamate is formed <it>via </it>a catalytic cycle, which involves activation of the DMC by a key active intermediate species, formed from the coordination of the carbonyl oxygen with Zn(II), as well as a reaction intermediate formed from the nucleophilic attack of the amino group on the carbonyl carbon.</p

The Bishopric of Bamberg in the Medieval World

Der Band „Das Bistum Bamberg in der Welt des Mittelalters“ bietet den um bibliographische Hinweise erweiterten Text der Vorträge, die im Rahmen der Ringvorlesung des Zentrums für Mittelalterstudien (ZEMAS) der Universität Bamberg im Jahr des tausendjährigen Bestehens der (Erz-)Diözese Bamberg gehalten wurden. Ausführlich behandelt wird die Gründung des Bistums 1007 und seine Entwicklung im weiteren Verlauf des Mittelalters. Neben den historischen kommen auch baugeschichtliche, kunsthistorische und literaturgeschichtliche Aspekte zur Sprache. Alle Vorträge sind vergleichend angelegt und zeigen auf, in welche größeren Prozesse Gründung und Entwicklung des Bistums Bamberg sich einfügen. Der Blick reicht daher von Bamberg und Oberfranken über Merseburg, Magdeburg, Prag, Regensburg, Kärnten, Konstanz und Eger bis nach Burgund, Istrien, Apulien und in die Werkstätten arabischer Elfenbeinschnitzer in Andalusien.The volume "The Diocese of Bamberg in the Medieval World" collects extended versions of papers presented in the Centre for Medieval Studies (ZEMAS) at the university of Bamberg lecture series commemorating the millenary anniversary of the (arch) diocese of Bamberg. The lectures address, in detail, the founding of the diocese in 1007 and its subsequent development over the course of the Middle Ages. Employing an interdisciplinary approach, the papers emphasize political history, architectural history, art history, and literary history. All the lectures are presented comparatively and demonstrate how the foundation and the development of the diocese of Bamberg are integrated in larger processes and developments. This perspective extends the scope of these papers from Bamberg and Upper Franconia to Merseburg, Magdeburg, Prague, Regensburg, Carinthia (Austria), Constance, and Cheb (Czech Republic) to Burgundy (France), Apulia (Italy), Istria (Croatia), and the workshops of Arab ivory carvers in Andalusia

Lung vasodilatory response to inhaled iloprost in experimental pulmonary hypertension: amplification by different type phosphodiesterase inhibitors

Inhaled prostanoids and phosphodiesterase (PDE) inhibitors have been suggested for treatment of severe pulmonary hypertension. In catheterized rabbits with acute pulmonary hypertension induced by continuous infusion of the stable thromboxane analogue U46619, we asked whether sildenafil (PDE1/5/6 inhibitor), motapizone (PDE3 inhibitor) or 8-Methoxymethyl-IBMX (PDE1 inhibitor) synergize with inhaled iloprost. Inhalation of iloprost caused a transient pulmonary artery pressure decline, levelling off within <20 min, without significant changes in blood gases or systemic hemodynamics. Infusion of 8-Methoxymethyl-IBMX, motapizone and sildenafil caused each a dose-dependent decrease in pulmonary artery pressure, with sildenafil possessing the highest efficacy and at the same time selectivity for the pulmonary circulation. When combining a per se ineffective dose of each PDE inhibitor (200 μg/kg × min 8-Methoxymethyl-IBMX, 1 μg/kg × min sildenafil, 5 μg/kg × min motapizone) with subsequent iloprost nebulization, marked amplification of the prostanoid induced pulmonary vasodilatory response was noted and the area under the curve of P(PA )reduction was nearly threefold increased with all approaches, as compared to sole iloprost administration. Further amplification was achieved with the combination of inhaled iloprost with sildenafil plus motapizone, but not with sildenafil plus 8MM-IBMX. Systemic hemodynamics and gas exchange were not altered for all combinations. We conclude that co-administration of minute systemic doses of selective PDE inhibitors with inhaled iloprost markedly enhances and prolongs the pulmonary vasodilatory response to inhaled iloprost, with maintenance of pulmonary selectivity and ventilation perfusion matching. The prominent effect of sildenafil may be operative via both PDE1 and PDE5, and is further enhanced by co-application of a PDE3 inhibitor